Selective targeting of PPAR? by the natural product chelerythrine with a unique binding mode and improved antidiabetic potency.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is a pervasive metabolic syndrome that is characterized by insulin resistance, hyperglycemia and dyslipidemia. As full agonists of PPAR?, thiazolidinedione (TZD) drugs elicit antidiabetic effects by targeting PPAR? but is accompanied by weight gain, fluid retention and cardiovascular risk associated with their transcriptional agonism potency. We here identify a natural product chelerythrine as a unique selective PPAR modulator (SPPARM) with a potent PPAR? binding activity but much less classical receptor transcriptional agonism. Structural analysis reveals that chelerythrine exhibits unique binding in parallel with H3 of PPAR?. Unlike TZDs, chelerythrine destabilizes helix 12, especially residue tyrosine 473, resulting in a loose configuration of AF-2 and a selective cofactor profile distinct from TZDs, leading to a differential target gene profile in adipogenesis in db/db diabetic mice. Moreover, chelerythrine improved insulin sensitivity by more potently blocking the phosphorylation of PPAR? by CDK5 compared to TZDs. These data fundamentally elucidate the mechanism by which chelerythrine retains the benefits of improving insulin sensitivity while reducing the adverse effects of TZDs, suggesting that the natural product chelerythrine is a very promising pharmacological agent by selectively targeting PPAR? for further development in the clinical treatment of insulin resistance.

SUBMITTER: Zheng W 

PROVIDER: S-EPMC4505335 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature